1. Field of the Invention
This invention relates to the synthesis of a polycaprolactone fumarate copolymer useful as a material for a biocompatible scaffold for tissue engineering.
2. Description of the Related Art
Segmental nerve injuries are quite common, and the autologous nerve graft remains the gold standard in the field of peripheral nerve surgery. However, due to lack of availability of autologous nervous tissue, alternative structures have been proposed for use in the treatment of nerve defects.
Synthetic guidance conduits can be used for nerve defects of less than three centimeters. Available synthetic nerve conduits include: polyglycolic acid (PGA) conduits (e.g., Neurotube™ conduit); polylactide-co-caprolactone (PLCL) conduits (e.g., Neurolac™ conduit); collagen conduits (e.g., Neurogen™ and Neuromatrix™ conduits) and polyvinyl alcohol (PVA) conduits (e.g., SaluBridge™ conduit). Nerve guidance conduits are mainly non-permeable which limits the flux of molecules through polymer, and the flux varies between molecules and polymers. Non-permeable conduits limit the exchange of nutrients and cellular waste within the conduit, and repair of longer defects may require enhanced conduit permeability.
Even though nerve conduits can be used to repair segmental nerve defects, defects larger than three centimeters are challenging. It has become increasingly believed that porous nerve conduit walls enhance regeneration. Porous nerve conduits are reported in the literature. Example porous nerve conduit materials include: (i) high permeability polycaprolactone (see Rodriguez et al., Biomaterials 1999, 20, 1489-500); (ii) low permeability polycaprolactone (see Rodriguez et al., Biomaterials 1999, 20, 1489-500); (iii) porous poly(lactic-co-glycolic acid) (see Cai et al., J Biomed Mater Res A 2005, 75, 374-86); and (iv) porous gelatin (see Chang et al., Artif Organs 2009, 33, 1075-85). Nonporous, macroporous, and microporous scaffolds have also been reported in Vleggeert-Lankamp et al., J Biomed Mater Res A 2007, 80, 965-82, and for a six millimeter defect, the best scaffold was microporous, and 60% possessed nerve cable. However, both microporous and macroporous scaffolds had fibrous tissue infiltration which is a disadvantage.
Techniques for creating porous nerve conduit structures have been limited to porogen leaching techniques which result in microporosity, typically five microns and larger. Not only are the pores larger than five microns (and many times tens to hundreds of microns), the pores are also random which allows fibrous tissue infiltration and uncontrolled diffusion of all molecules through the porous walls. Also, high porosity is required (>80% porosity) to reach interconnected porosity resulting in compromised mechanical properties. Thus, existing porous nerve conduit structures exhibit one or more of the following problems: fibrous tissue infiltration, uncontrolled diffusion of all molecules through the porous walls, and compromised mechanical properties.
Nanoporous materials have numerous applications in nonmedical industries for uses such as membranes, surface patterning, and templates for inorganic materials. These applications have typically used block copolymer (e.g., an A-B block copolymer) self-assembly wherein the block copolymers assemble by phase separation of A and B blocks to form nanostructures. Although these types of nanomaterials are widely used in other industries, they have yet to find a robust approach for incorporation into the biomaterials field.
Polycaprolactone fumarate (PCLF) is a cross-linkable derivative of polycaprolactone (PCL) that has been shown to be promising material for tissue engineering applications involving both the repair of segmental nerve defects as well as a bone substitute. PCLF also has potential as a drug delivery vehicle. PCLF has been used for the production of nerve conduits to repair segmental nerve defects. These PCLF nerve conduits have been shown to support robust nerve regeneration across the one centimeter rat sciatic nerve defect model and have warranted future clinical studies.
What is needed therefore is an improved biocompatible polycaprolactone fumarate formulation that can be used to manufacture a nerve conduit that does not allow for fibrous tissue infiltration, that controls diffusion of molecules through the nerve conduit wall, and that has acceptable mechanical properties.